Radiation Mitigation and Normal Tissue Stem Cells

项目总结 这项研究项目的长期目标是确定正常组织干细胞通过哪些机制 最初幸存下来的辐射是在体内扩张，以保持组织的完整性。这项提案的目标是 目的是揭示含有磺酰基哌嗪活性基团的药物缓解作用的机制。我们 将调查在应用这些技术后正常组织干细胞库的重建情况 缓释剂对肠道和中枢神经系统(CNS)中的干细胞群体有直接影响，或 通过为干细胞扩增提供允许的微环境来进行调节。使用体外和体内模型 急性和晚期辐射损伤的系统，我们将调查这些药物对 干细胞的扩增和可塑性，并揭示导致辐射缓解的潜在信号事件。 具体地说，我们假设含有磺酰基哌嗪活性基团的辐射缓蚀剂 之前的资助期，直接或间接影响肠道和中枢神经系统的正常组织干细胞数量 通过G蛋白偶联受体介导的信号转导。细胞效应的系统研究 化合物#15在缓解ARS和DEARE并揭示潜在机制方面将为 发现和理解治疗急性辐射综合征(ARS)和延迟的新型双功能缓释剂 急性辐射暴露的影响(DEARE)。这将对该领域产生广泛影响，因为它将揭示 可用于减轻多器官辐射损伤的正常组织干细胞的常见靶点 系统同时运行。

PROJECT SUMMARY The long-term goal of this research project is to identify mechanisms by which normal tissue stem cells that initially survive exposure to radiation are expanded in vivo to maintain tissue integrity. The goal of this proposal is to uncover the mechanism of mitigation observed with drugs containing sulfonylpiperazine active groups. We will investigate whether the reconstitution of the normal tissue stem cell pool seen after application of these mitigators is a direct effect on the stem cell populations in the gut and central nervous system (CNS), or mediated by providing a microenvironment permissive for stem cell expansion. Using in vitro and in vivo model systems for acute and late radiation damage we will investigate direct and indirect effects of these drugs on stem cell expansion and plasticity and uncover the underlying signaling events that lead to radiation mitigation. Specifically, we hypothesize that radiation mitigators with sulfonylpiperazine active groups, identified in the previous funding period, affect normal tissue stem cell populations in the gut and CNS directly or indirectly through G-protein-coupled receptor-mediated signaling. The systematic study of the cellular effects of compound #15 in mitigating ARS and DEARE, and uncovering the underlying mechanisms will lay ground for finding and understanding novel dual function mitigators for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). This will have a wide impact on the field, as it will uncover common targets on normal tissue stem cells that can be used to mitigate radiation damage on multiple organ systems simultaneously.